The central question addressed in our studies is whether a low nutritional status of essential fatty acids increases the predisposition to psychiatric disorders including depression and schizophrenia or to pathological behaviors such as homicide and suicide. Some essential fatty acids, in particular docosahexaenoic acid (DHA), are selectively concentrated in the brain, but these nutrients are ultimately available only from dietary sources e.g. seafood, which is rich in this omega-3 fatty acid. During the time period covered by this report, 14 manuscripts have been prepared and submitted for publication. In addition, a double blind placebo controlled clinical trial was planned and approved in April 2001. In this protocol, entitled Polyunsaturated Fatty Acids and the Neurochemistry of Cardiovascular and Motor Reactivity, aggressive subjects will be given either 3.8 gm/d of EPA and DHA or a placebo. The key questions of the protocol are to assess if this treatment will reduce 1) aggressive behaviors, 2) improve neurochemical measures of serotinergic function 3) improve cardiovascular measures thought to be associated with depressive and violent behaviors. Both before and after receiving the omega-3 fatty acids or the placebo, subjects will undergo the following evaluations: 1) Laboratory defined measures of aggressive behavior, 2) A lumbar puncture for evaluation of cerebrospinal fluid, 3) measures of heart rate variability. Subjects are actively being recruited for screening evaluations for this protocol. Our projects have examined the question of the role of omega-3 fatty acids in psychiatric disorders from several perspectives: population comparisons in epidemiological studies, clinical interventional studies in adults with psychiatric disorders, and observational studies of the relationship of essential fatty acids status to the function of key neurotransmitter systems. In addition to the status of adults, nutritional inadequacies both in early development may also contribute to an increased predisposition toward psychiatric disorders or abnormal behaviors. Thus, we have also conducted two developmental outcome studies. 1) A four-decade follow up study examined the maternal essential fatty acid status at the time of birth and the lifetime risk of developing schizophrenia. 2) An intervention study that examined the effects of supplementing infant formulas with DHA and arachidonic acid (AA) on the short and long term consequences to neurological development among rhesus monkeys. The cross-national ecological studies that have compared the rates of seafood consumption to prevalence rates of psychiatric disorders indicate that there may be a specific relationship to prevalence rates of affective and impulsive disorders, but not to schizophrenia. In a prior study, we reported that seafood consumption predicted lower prevalence rates of major depression over a nearly 60-fold range across countries. Consistent with this report we found that bipolar spectrum disorders (manic depressive disorders) have a well-defined relationship to seafood consumption with an apparent threshold of approximately 75 lbs/person/yr. Below this level of national average consumption, the prevalence rates of bipolar disorder rise precipitously from 0.04% in Taiwan (81.6 lbs/person/y) to 6.5% in Germany (27.6 lbs/person/y) a nearly 60-fold difference in prevalence. We conducted each of these studies using data from a gold standard of psychiatric epidemiological studies, the Epidemiological Catchment Area Study. Two studies within countries yielded similar results. 1) In collaboration with Antti Tanskanen, M.D., Ph.D., we studied a population of 1,767 subjects within Northern Finland. We found that subjects who consumed fish twice a week or more were at lower risk of reporting depressive symptoms (odds ratio 0.63) and suicidal thinking (odds ratio 0.57), compared to infrequent fish consumers. The subjects who consumed vegetable oils were more than twice as likely to report being depressed compared to those with no consumption. This is significant because vegetable oils are high in omega-6 fatty acids that compete with the effects of omega-3 fatty acids. 2) We again found similar results among a community sample of 200 elderly subjects that represented 80% of the elderly people in two counties in Iowa. Low plasma concentrations of plasma DHA alone significantly predicted more severe sleep complaints and reports of anxiety as well as depression among women. A series of four studies done by our group have indicated that there is no relationship between essential fatty acid status and schizophrenia. 1) Across 14 countries, there was no significant relationship between prevalence rates of schizophrenia and seafood consumption using Epidemiological Catchment Area data. 2) These cross-national data are consistent with the results of a double-blind, placebo-controlled multi-center trial we conducted among 74 chronic schizophrenics (In collaboration with the Stanley Foundation). No clinical improvements were found in patients consuming supplements of 3 g/d of EPA relative to 3 g/d of mineral oil for 4 months. 3) We examined the essential fatty acid composition of maternal plasma drawn on the day of birth comparing 51 control mothers to mothers of 27 children that developed psychosis over the next four decades. In contrast to the predicted hypothesis, the mothers of children who developed psychosis were not deficient in any essential fatty acid. 4) We found that smoking markedly lowered erythrocyte fatty acid DHA concentrations. This is significant because eight prior reports that schizophrenics who smoked had lower RBC, DHA concentrations, but they did not control for the numbers of smokers in the schizophrenic and control populations. In summary, these data suggest that there could be a specific relationship of seafood consumption and omega-3 status to prevalence rates of affective and impulsive disorders, but not to the prevalence of schizophrenia or to biochemical abnormalities associated with schizophrenia. Three of our recent studies indicate that inadequate omega-3 fatty acid consumption may contribute to an increased risk of mortality from suicide and homicide. 1) Across 31 countries, greater seafood consumption predicts a lower risk of death due to suicide. 2) Among suicide attempters, low concentrations of the omega-3 fatty acid eicosapentaenoic acid (EPA) alone were robustly correlated with greater psychopathology scores. 3) Finally, in a cross-national analysis, higher homicide mortality rates were correlated to lower rates of seafood consumption across 26 countries in a cross-national analysis. The diagnosis of death due to homicide is subject to fewer cross-national cultural differences than are other behavioral outcomes. These data also are consistent with observational and interventional data for violence and hostility published by other investigators. Infant formula studies The cross-national correlational relationships do not indicate if an increased predisposition towards impulsive and depressive behaviors occurs only in adulthood, or is a long-term consequence of a nutritional deficiency during early development. In prior experiments it has been established that separating rhesus infants from their mothers at birth and raising them in a nursery imparts a lifetime predisposition toward abnormal and aggressive behaviors. We noted that while in the nursery the infants are fed formulas that are virtually devoid of DHA and AA. Thus, we compared two groups of infant rhesus monkeys that were removed from their mothers at birth and were raised in a stringently controlled nursery for the first six months. This study is ongoing.